CXCL9, also known as CXCL9 (monokine induced by IFN-γ), was first discovered from the mouse macrophage cell line RAW 264.7 in 1990 [1]. It is a member of the CXC subfamily of chemokines, characterized by its first two cysteines being separated by a single amino acid. In vivo, CXCL9 is produced by macrophages in response to IFN-γ, but not in response to other macrophage activators including IFN-α, IFN-β and LPS. CXCL9 is known as a chemoattractant for activated T lymphocytes [2], tumor-infiltrating lymphocytes [3] as well as NK cells and TH1 lymphocytes [4]. CXCL9 has been investigated primarily for its function in autoimmune diseases [6], allograft rejection [7] and cancer therapy [8].
Aside from the above mentioned functions in the immune system, CXCL9 also has two other known functions. First, CXCL9 is an angiostatic agent [10,11]. Zhang et al. designed a gene therapy method based on the anti-angiogenic effect of CXCL9 in tumors [8]. They combined pORF-CXCL9 with low-dose cisplatin to treat tumors and the combination showed significant antitumor activity. Second, CXCL9 inhibits proliferation of myeloid progenitors stimulated by multiple growth factors in vitro [5,9]. Many CXC chemokines, for example PF4 (platelet factor), have myelosuppressive activity [5]. Further, CXCR3 expression is up regulated in hematopoietic cells stimulated by factors such as G-CSF [12].
Myelosuppression is the main reason for the lethal side effects of chemotherapy or radiotherapy of cancer. Many drugs have been developed to deal with myelosuppression. Up to now, two approaches have been used to protect bone marrow from the toxicity of chemotherapy or radiotherapy. In one approach, positive regulators are administrated prior to therapy to stimulate the proliferation of critical stem cells, progenitor cells or end-stage hematopoietic cells. These positive regulators, including IL-6 [13] and CSFs [14,15], can result in an increase of hematopoietic cells before chemotherapy, thus allowing a more rapid recovery. Another approach is to administer these regulators post chemotherapy or radiotherapy, to enhance the proliferation of hematopoietic cells, also resulting in a better recovery.
There remains a need to develop new compositions and methods to prevent or reduce myelosuppression as well as to improve recovery from myelosuppression caused by chemotherapy, radiation therapy, and other myelotoxic agents.